Arteries are the large blood vessels that carry oxygenated blood away from the heart to all the tissues and organs in the body. They are integral to the proper function of each organ since their disruption severely compromises the ability of each tissue to perform. As with all blood vessels, arteries contain a single endothelial cell layer facing the blood lumen (tunica intima), but, in addition, they have several concentric layers of smooth muscle, which makes up the majority of the artery (tunica media) and provides it with structural integrity and contractility. In most arteries the endothelial cell layer is separated from the smooth muscle cell layer by an internal elastic membrane. Furthermore, elastic fibers and other structural components are embedded within the smooth muscle cell layers. This allows arteries to remain compliant in response to the pulsatile blood flow found directly downstream of the heart. The outer layer of the arterial wall entails an adventitial layer of fibroblasts embedded in a collagen matrix (tunica externa). Despite the relatively constant structure of arteries serving each organ, their construction during development can vary from site to site in terms of cellular origins and morphogenesis. Because of this heterogeneity, there is still much to learn about the development and biological regulation of organ-specific arteries.
Angiogenesis and vasculogenesis are processes involved in the growth of blood vessels. Angiogenesis is the process by which new blood vessels are formed from extant capillaries, while vasculogenesis involves the growth of vessels deriving from endothelial progenitor cells. Angiogenesis and vasculogenesis, and the factors that regulate these processes, are important in embryonic development, inflammation, and wound healing, and also contribute to pathologic conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis, and chronic inflammatory diseases.
Microvascular perivascular cells (“pericytes”) are defined by their location in vivo. The pericyte is a small ovoid shaped cell with many finger-like projections that parallel the capillary axis and partially surround an endothelial cell in a microvessel. Pericytes share a common basement membrane with the endothelial cell. Pericytes are elongated cells with the power of contraction that have been observed to have a variety of functional characteristics. Some of the pericyte functional characteristics observed in vivo and in vitro are that they regulate endothelial cell proliferation and differentiation, contract in a manner that either exacerbates or reduces endothelial cell junction inflammatory leakage, synthesize and secrete a wide variety of vasoactive autoregulating agonists, and synthesize and release structural constituents of the basement membrane and extracellular matrix.
Pericytes play an important role in angiogenesis and vessel maturation. During angiogenesis pericytes prevent vessel regression and promote endothelial quiescence. Generally, high pericyte coverage is observed in peripheral tissues, supporting a role of pericytes in regulating orthostatic blood pressure. High pericyte coverage also correlates with barrier function for instance in the blood-brain barrier and a low endothelial turnover rate. Therefore, besides a general role in vessel formation, pericytes seem to have tissue-specific function including endothelial barrier function and blood pressure regulation of microvessels. While the role of pericytes has been extensively studied during angiogenesis, less is known about their involvement in arteriogenesis.
The vasculature is a network of endothelial-lined tubes covered with mural cells where pericytes associate with small vessels and smooth muscle surrounds larger arteries and veins. Because these cells exist in close proximity, vascular biologists have long wondered whether pericytes and smooth muscle cells interconvert. However, direct evidence has been restricted by limited experimental tools and a lack of knowledge about when and where such differentiation events might occur. Knowing whether pericytes and smooth muscle differentiate into each other, and the mechanisms that stimulate this process, has the potential to impact clinical treatments for cardiovascular disease. Our research has discovered that in the heart during embryonic development, pericytes are the progenitors of coronary artery smooth muscle, and that Notch signaling stimulates the pericyte to smooth muscle transition. Understanding coronary artery biology could identify clinical treatments for coronary artery disease.
Coronary artery smooth muscle development remains a poorly understood process. Current methods of coronary artery regeneration fail to produce meaningful repair following cardiovascular injury, because of a lack of knowledge on progenitor cell populations and the signaling pathways that activate their differentiation. The discovery that pericytes are epicardial-derived coronary artery smooth muscle progenitors could have implications for regenerative medicine, as this knowledge could reveal new progenitor cells and targetable pathways for coronary disease.